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[PMID]:29175453
[Au] Autor:Zhang Y; Lickteig AJ; Csanaky IL; Klaassen CD
[Ad] Endereço:School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: youcai.zhang@tju.edu.cn.
[Ti] Título:Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.
[So] Source:Toxicol Appl Pharmacol;338:112-123, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Bile/metabolismo
Fígado/metabolismo
PPAR alfa/fisiologia
[Mh] Termos MeSH secundário: Animais
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Clofibrato/farmacologia
Feminino
Íleo/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (PPAR alpha); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:29190422
[Au] Autor:Zhao Y; Liu J; Hao W; Zhu H; Liang N; He Z; Ma KY; Chen ZY
[Ad] Endereço:Food & Nutritional Sciences Programme, School of Life Sciences, The Chinese University of Hong Kong , Shatin, New Territories, Hong Kong, China.
[Ti] Título:Structure-Specific Effects of Short-Chain Fatty Acids on Plasma Cholesterol Concentration in Male Syrian Hamsters.
[So] Source:J Agric Food Chem;65(50):10984-10992, 2017 Dec 20.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies have shown that short-chain fatty acids (SCFAs) are capable of decreasing plasma cholesterol. However, the relative plasma-cholesterol-lowering activity of individual SCFAs and the underlying mechanisms by which SCFAs decrease plasma cholesterol remain largely unknown. The present study was done to compare the plasma-cholesterol-lowering potencies of four common SCFAs with 2-5 carbons and to investigate their interactions with gene expressions of key regulatory factors involved in cholesterol metabolism. For 6 weeks, five groups of male Golden hamsters were fed either a control high-cholesterol diet (HCD) or one of the four experimental HCDs containing 0.5 mol of acetate (Ac), propionate (Pr), butyrate (Bu), or valerate (Va) per kilogram of the diet. The results showed that Ac, Pr, and Bu significantly reduced plasma total cholesterol (TC) by 24, 18, and 17% (P < 0.05), respectively. All four SCFAs could decrease non-HDL cholesterol (non-HDL-C) and the non-HDL-C/HDL-C ratio. The addition of Ac, Pr, or Bu into the diet significantly promoted fecal excretion of bile acids by 121, 113, or 120% (P < 0.05), respectively, and upregulated the gene expressions of sterol-regulatory-element-binding protein 2 (SREBP2), low-density-lipoprotein receptor (LDLR), and cholesterol 7α-hydroxylase (CYP7A1) in the liver. It was concluded that SCFAs with 2-4 carbons (Ac, Pr, and Bu) are more hypocholesterolemic than Va, which has 5 carbons, via enhancing fecal excretion of bile acids and promoting the hepatic uptake of cholesterol from the blood.
[Mh] Termos MeSH primário: Anticolesterolemiantes/administração & dosagem
Colesterol/sangue
Ácidos Graxos Voláteis/administração & dosagem
Hipercolesterolemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticolesterolemiantes/química
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Cricetinae
Ácidos Graxos Voláteis/química
Seres Humanos
Hipercolesterolemia/sangue
Hipercolesterolemia/genética
Hipercolesterolemia/metabolismo
Masculino
Mesocricetus
Receptores de LDL/genética
Receptores de LDL/metabolismo
Proteína de Ligação a Elemento Regulador de Esterol 2/genética
Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Fatty Acids, Volatile); 0 (Receptors, LDL); 0 (Sterol Regulatory Element Binding Protein 2); 0 (Triglycerides); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b04666


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[PMID]:28749691
[Au] Autor:Flesch D; Cheung SY; Schmidt J; Gabler M; Heitel P; Kramer J; Kaiser A; Hartmann M; Lindner M; Lüddens-Dämgen K; Heering J; Lamers C; Lüddens H; Wurglics M; Proschak E; Schubert-Zsilavecz M; Merk D
[Ad] Endereço:Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
[Ti] Título:Nonacidic Farnesoid X Receptor Modulators.
[So] Source:J Med Chem;60(16):7199-7205, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
[Mh] Termos MeSH primário: Imidazóis/farmacologia
Piridinas/farmacologia
Receptores Citoplasmáticos e Nucleares/metabolismo
[Mh] Termos MeSH secundário: Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/genética
Animais
Colesterol 7-alfa-Hidroxilase/genética
Estabilidade de Medicamentos
Células HEK293
Células HeLa
Células Hep G2
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Imidazóis/metabolismo
Masculino
Proteínas de Membrana Transportadoras/genética
Simulação de Acoplamento Molecular
PPAR alfa/genética
Piridinas/síntese química
Piridinas/química
Piridinas/metabolismo
Ratos Sprague-Dawley
Receptores Citoplasmáticos e Nucleares/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (6-chloro-2-(4-chloropyridin-2-yl)-N-(4-methoxybenzyl)imidazo(1,2-a)pyridin-3-amine); 0 (ABCB11 protein, human); 0 (ATP Binding Cassette Subfamily B Member 11); 0 (ATP-Binding Cassette Transporters); 0 (Imidazoles); 0 (Membrane Transport Proteins); 0 (PPAR alpha); 0 (Pyridines); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Sterol Regulatory Element Binding Protein 1); 0 (farnesoid X-activated receptor); 0 (nuclear receptor subfamily 0, group B, member 2); 0 (organic solute transporter alpha, human); 7K383OQI23 (zolpidem); EC 1.14.14.23 (CYP7A1 protein, human); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00903


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[PMID]:28935756
[Au] Autor:Trenteseaux C; Gaston AT; Aguesse A; Poupeau G; de Coppet P; Andriantsitohaina R; Laschet J; Amarger V; Krempf M; Nobecourt-Dupuy E; Ouguerram K
[Ad] Endereço:From the UMR 1280 Physiopathologie des Adaptations Nutritionnelles, INRA, Université de Nantes, France (C.T., G.P., P.d.C., V.A., M.K., E.N.-D., K.O.); Centre de Recherche en Nutrition Humaine Ouest, Nantes, France (C.T., A.A., M.K., K.O.); UMR1063 Stress Oxydant et Pathologies Métaboliques, INSERM,
[Ti] Título:Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids.
[So] Source:Arterioscler Thromb Vasc Biol;37(11):2053-2063, 2017 Nov.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. APPROACH AND RESULTS: Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic and but higher gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in and gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower gene expression compared with female born to normocholesterolemic mothers. DNA methylation of , and promoter regions was slightly modified and may explain the mRNA expression modulation. CONCLUSIONS: Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
[Mh] Termos MeSH primário: Doenças da Aorta/metabolismo
Aterosclerose/metabolismo
Ácidos e Sais Biliares/metabolismo
Hipercolesterolemia/metabolismo
Metilaminas/metabolismo
Efeitos Tardios da Exposição Pré-Natal
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Animais Recém-Nascidos
Aorta/metabolismo
Aorta/patologia
Doenças da Aorta/etiologia
Doenças da Aorta/genética
Doenças da Aorta/patologia
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Aterosclerose/etiologia
Aterosclerose/genética
Aterosclerose/patologia
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Metilação de DNA
Modelos Animais de Doenças
Feminino
Vesícula Biliar/metabolismo
Predisposição Genética para Doença
Hipercolesterolemia/complicações
Hipercolesterolemia/genética
Fígado/metabolismo
Masculino
Camundongos Knockout
Oxigenases/genética
Oxigenases/metabolismo
Fenótipo
Placa Aterosclerótica
Gravidez
Regiões Promotoras Genéticas
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores de LDL/genética
Receptores de LDL/metabolismo
Receptores Depuradores Classe B/genética
Receptores Depuradores Classe B/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Bile Acids and Salts); 0 (Methylamines); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, LDL); 0 (Scarb1 protein, mouse); 0 (Scavenger Receptors, Class B); 0 (farnesoid X-activated receptor); 97C5T2UQ7J (Cholesterol); EC 1.13.- (Oxygenases); EC 1.14.13.8 (dimethylaniline monooxygenase (N-oxide forming)); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309923


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[PMID]:28891815
[Au] Autor:Tarling EJ; Clifford BL; Cheng J; Morand P; Cheng A; Lester E; Sallam T; Turner M; de Aguiar Vallim TQ
[Ad] Endereço:Department of Medicine, Division of Cardiology, and.
[Ti] Título:RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism.
[So] Source:J Clin Invest;127(10):3741-3754, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bile acids function not only as detergents that facilitate lipid absorption but also as signaling molecules that activate the nuclear receptor farnesoid X receptor (FXR). FXR agonists are currently being evaluated as therapeutic agents for a number of hepatic diseases due to their lipid-lowering and antiinflammatory properties. FXR is also essential for maintaining bile acid homeostasis and prevents the accumulation of bile acids. Elevated bile acids activate FXR, which in turn switches off bile acid synthesis by reducing the mRNA levels of bile acid synthesis genes, including cholesterol 7α-hydroxylase (Cyp7a1). Here, we show that FXR activation triggers a rapid posttranscriptional mechanism to degrade Cyp7a1 mRNA. We identified the RNA-binding protein Zfp36l1 as an FXR target gene and determined that gain and loss of function of ZFP36L1 reciprocally regulate Cyp7a1 mRNA and bile acid levels in vivo. Moreover, we found that mice lacking hepatic ZFP36L1 were protected from diet-induced obesity and steatosis. The reduced adiposity and antisteatotic effects observed in ZFP36L1-deficient mice were accompanied by impaired lipid absorption that was consistent with altered bile acid metabolism. Thus, the ZFP36L1-dependent regulation of bile acid metabolism is an important metabolic contributor to obesity and hepatosteatosis.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Proteínas Nucleares/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/genética
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Fígado Gorduroso/induzido quimicamente
Fígado Gorduroso/genética
Fígado Gorduroso/metabolismo
Camundongos
Camundongos Knockout
Proteínas Nucleares/deficiência
Obesidade/induzido quimicamente
Obesidade/genética
Obesidade/metabolismo
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Nuclear Proteins); 0 (RNA-Binding Proteins); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Zfp36l1 protein, mouse); 0 (farnesoid X-activated receptor); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


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[PMID]:28877164
[Au] Autor:Han K; Bose S; Wang JH; Lim SK; Chin YW; Kim YM; Choi HS; Kim H
[Ad] Endereço:Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, Goyang, Gyeonggi-do, Republic of Korea.
[Ti] Título:In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis.
[So] Source:PLoS One;12(9):e0182467, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The radix of Scutellaria baicalensis (SB) is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti-diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day) alone with co-administration of metformin (100 mg/5 mL/kg/day) and SB extract (200 mg/5 mL/kg/day) on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Homeostase/efeitos dos fármacos
Metformina/farmacologia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Algoritmos
Animais
Glicemia/metabolismo
Western Blotting
Peso Corporal/efeitos dos fármacos
Colesterol/sangue
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Terapia Combinada
Fezes/química
Comportamento Alimentar/efeitos dos fármacos
Microbioma Gastrointestinal/efeitos dos fármacos
Resistência à Insulina
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Metagenoma
Metformina/administração & dosagem
Filogenia
Extratos Vegetais/administração & dosagem
Análise de Componente Principal
Ratos Endogâmicos OLETF
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Blood Glucose); 0 (Plant Extracts); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Scutellaria baicalensis extract); 0 (farnesoid X-activated receptor); 9100L32L2N (Metformin); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (CYP7A1 protein, rat); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182467


  7 / 1332 MEDLINE  
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[PMID]:28645914
[Au] Autor:Cheng Y; Chen S; Freeden C; Chen W; Zhang Y; Abraham P; Nelson DM; Humphreys WG; Gan J; Lai Y
[Ad] Endereço:Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey yaofeng.cheng@BMS.com.
[Ti] Título:Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.
[So] Source:J Pharmacol Exp Ther;362(3):385-394, 2017 Sep.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/genética
Ácidos e Sais Biliares/metabolismo
Cromanos/farmacologia
Homeostase/efeitos dos fármacos
Homeostase/genética
Hipoglicemiantes/farmacologia
Tiazolidinedionas/farmacologia
[Mh] Termos MeSH secundário: Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
Animais
Bile/metabolismo
Colesterol 7-alfa-Hidroxilase/biossíntese
Colesterol 7-alfa-Hidroxilase/genética
Técnicas de Inativação de Genes
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Ratos
Ratos Sprague-Dawley
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP Binding Cassette Subfamily B Member 11); 0 (Abcb11 protein, rat); 0 (Bile Acids and Salts); 0 (Chromans); 0 (Hypoglycemic Agents); 0 (RNA, Messenger); 0 (Thiazolidinediones); EC 1.14.14.23 (CYP7A1 protein, rat); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); I66ZZ0ZN0E (troglitazone)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.242370


  8 / 1332 MEDLINE  
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[PMID]:28623919
[Au] Autor:Saad DY; Soliman MM; Baiomy AA; Yassin MH; El-Sawy HB
[Ad] Endereço:Medical Laboratory Department, Faculty of Applied Medical Sciences, Taif University, Turabah, Saudi Arabia.
[Ti] Título:Effects of Karela (Bitter Melon; Momordica charantia) on genes of lipids and carbohydrates metabolism in experimental hypercholesterolemia: biochemical, molecular and histopathological study.
[So] Source:BMC Complement Altern Med;17(1):319, 2017 Jun 17.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hypercholesterolemia is a serious diseases associated with type-2 diabetes, atherosclerosis, cardiovascular disorders and liver diseases. Humans seek for safe herbal medication such as karela (Momordica charantia/bitter melon) to treat such disorders to avoid side effect of pharmacotherapies widely used. METHODS: Forty male Wistar rats were divided into four equal groups; control group with free access to food and water, cholesterol administered group (40 mg/kg BW orally); karela administered group (5 g /kg BW orally) and mixture of cholesterol and karela. The treatments continued for 10 weeks. Karela was given for hypercholesterolemic rats after 6 weeks of cholesterol administration. Serum, liver and epididymal adipose tissues were taken for biochemical, histopathological and genetic assessments. RESULTS: Hypercholesterolemia induced a decrease in serum superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and an increase in malondialdehyde (MDA) levels that were ameliorated by karela administration. Hypercholesterolemia up regulated antioxidants mRNA expression and altered the expression of carbohydrate metabolism genes. In parallel, hypercholesterolemic groups showed significant changes in the expression of PPAR-alpha and gamma, lipolysis, lipogenesis and cholesterol metabolism such as carnitine palmitoyltransferase-1 (CPT-1). Acyl CoA oxidase (ACO), fatty acids synthase (FAS), sterol responsible element binding protein-1c (SREBP1c), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) and cholesterol 7α-hydroxylase (CYP7A1) at hepatic and adipose tissue levels. Interestingly, Karela ameliorated all altered genes confirming its hypocholesterolemic effect. Histopathological and immunohistochemical findings revealed that hypercholesterolemia induced hepatic tissue changes compared with control. These changes include cholesterol clefts, necrosis, karyolysis and sever congestion of portal blood vessel. Caspase-3 immunoreactivity showed positive expression in hepatic cells of hypercholesterolemic rats compared to control. All were counteracted and normalized after Karela administration to hypercholesterolemic group. CONCLUSION: Current findings confirmed that karela is a potential supplement useful in treatment of hypercholesterolemia and its associated disorders and is good for human health.
[Mh] Termos MeSH primário: Metabolismo dos Carboidratos
Hipercolesterolemia/dietoterapia
Hipercolesterolemia/genética
Metabolismo dos Lipídeos
Momordica charantia/metabolismo
[Mh] Termos MeSH secundário: Tecido Adiposo/metabolismo
Animais
Anticolesterolemiantes/metabolismo
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Ácido Graxo Sintase Tipo I/genética
Ácido Graxo Sintase Tipo I/metabolismo
Seres Humanos
Hipercolesterolemia/enzimologia
Hipercolesterolemia/metabolismo
Fígado/metabolismo
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 2.3.1.85 (Fatty Acid Synthase, Type I)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170619
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-1833-x


  9 / 1332 MEDLINE  
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[PMID]:28549616
[Au] Autor:Zhu RG; Sun YD; Hou YT; Fan JG; Chen G; Li TP
[Ad] Endereço:Department of Food Science, College of Light Industry, Liaoning University, Liaoning Engineering Research Center for Food Bioprocessing, Shenyang Key Laboratory of Food Bioprocessing and Quality Control, Shenyang 110036, China. Electronic address: zhurugang@lnu.edu.cn.
[Ti] Título:Pectin penta-oligogalacturonide reduces cholesterol accumulation by promoting bile acid biosynthesis and excretion in high-cholesterol-fed mice.
[So] Source:Chem Biol Interact;272:153-159, 2017 Jun 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Haw pectin penta-oligogalacturonide (HPPS) has important role in improving cholesterol metabolism and promoting the conversion of cholesterol to bile acids (BA) in mice fed high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on cholesterol accumulation and the regulation of hepatic BA synthesis and transport in HCD-fed mice. Results showed that HPPS significantly decreased plasma and hepatic TC levels but increased plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, compared to HCD. BA analysis showed that HPPS markedly decreased hepatic and small intestine BA levels but increased the gallbladder BA levels, and finally decreased the total BA pool size, compared to HCD. Studies of molecular mechanism revealed that HPPS promoted hepatic ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor BI (SR-BI) expression but did not affect ATB binding cassette transporter G5/G8 (ABCG5/8) expression. HPPS inactivated hepatic farnesoid X receptor (FXR) and target genes expression, which resulted in significant increase of cholesterol 7α-hydroxylase 1 (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) expression, with up-regulations of 204.2% and 33.5% for mRNA levels, respectively, compared with HCD. In addition, HPPS markedly enhanced bile salt export pump (BSEP) expression but didn't affect the sodium/taurocholate co-transporting polypeptide (NTCP) expression. In conclusion, the study revealed that HPPS reduced cholesterol accumulation by promoting BA synthesis in the liver and excretion in the feces, and might promote macrophage-to-liver reverse cholesterol transport (RCT) but did not liver-to-fecal RCT.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Colesterol/sangue
Expressão Gênica/efeitos dos fármacos
Oligossacarídeos/farmacologia
Pectinas/farmacologia
[Mh] Termos MeSH secundário: Transportador 1 de Cassete de Ligação de ATP/genética
Transportador 1 de Cassete de Ligação de ATP/metabolismo
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Apolipoproteína A-I/sangue
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
HDL-Colesterol/sangue
Dieta Hiperlipídica
Intestino Delgado/efeitos dos fármacos
Intestino Delgado/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Camundongos
Pectinas/química
Receptores Depuradores Classe B/genética
Receptores Depuradores Classe B/metabolismo
Esteroide 12-alfa-Hidroxilase/genética
Esteroide 12-alfa-Hidroxilase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCA1 protein, mouse); 0 (ABCG1 protein, mouse); 0 (ATP Binding Cassette Transporter 1); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 1); 0 (Apolipoprotein A-I); 0 (Bile Acids and Salts); 0 (Cholesterol, HDL); 0 (Oligosaccharides); 0 (Pectins); 0 (Scarb1 protein, mouse); 0 (Scavenger Receptors, Class B); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); EC 1.14.18.8 (Steroid 12-alpha-Hydroxylase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE


  10 / 1332 MEDLINE  
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[PMID]:28498614
[Au] Autor:Slijepcevic D; Roscam Abbing RLP; Katafuchi T; Blank A; Donkers JM; van Hoppe S; de Waart DR; Tolenaars D; van der Meer JHM; Wildenberg M; Beuers U; Oude Elferink RPJ; Schinkel AH; van de Graaf SFJ
[Ad] Endereço:Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.
[So] Source:Hepatology;66(5):1631-1643, 2017 Nov.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Na -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. CONCLUSION: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Enterócitos/fisiologia
Fatores de Crescimento de Fibroblastos/metabolismo
Fígado/metabolismo
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Simportadores/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Colesterol 7-alfa-Hidroxilase/metabolismo
Regulação para Baixo
Feminino
Seres Humanos
Íleo/metabolismo
Lipopeptídeos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Isoformas de Proteínas/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Lipopeptides); 0 (Organic Anion Transporters, Sodium-Dependent); 0 (Protein Isoforms); 0 (Symporters); 0 (fibroblast growth factor 15, mouse); 0 (myrcludex-B); 145420-23-1 (sodium-bile acid cotransporter); 62031-54-3 (Fibroblast Growth Factors); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170513
[St] Status:MEDLINE
[do] DOI:10.1002/hep.29251



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